OP0103 GENE EXPRESSION PROFILES RETRIEVED FROM SINGLE CELL RNA SEQUENCING REVEAL PHENOTYPIC TRAITS IN PATIENTS WITH PSORIATIC ARTHRITIS INITIATING TUMOUR NECROSIS FACTOR ALPHA INHIBITOR AND INTERLEUKIN-17 INHIBITOR
Authors: M. Skougaard, C. Drachmann, Z. R. Stisen, S. B. Ditlev, L. E. Jessen, L. E. Kristensen
Journal: Annals of the Rheumatic Diseases (2022)

Background Patients with Psoriatic Arthritis (PsA) suffer from heterogenous debilitating symptoms caused by immune-mediated inflammation. However, great diversity in clinical response to available medical therapies targeting the immune response in PsA complicates treatment decision-making. Objectives The primary objective of the study was to evaluate gene expression profiles at baseline in responders versus non-responders of Tumour Necrosis Factors alpha inhibitor (TNFi) and Interleukin-17 inhibitor (IL-17i), respectively, to examine the foundation for future improved PsA patient stratification. Methods Single cell RNA sequencing (scRNAseq) was included to evaluate the transcriptome in responders versus non-responders of Tumour Necrosis Factor alpha inhibitor (TNFi) and Interleukin-17 inhibitor (IL-17i). Peripheral blood mononuclear cells (PBMCs) was isolated for scRNAseq and Disease Activity Score in PsA (DAPSA) retrieved in 40 PsA patients; 20 initiating TNFi and 20 initiating IL-17i. Responders and non-responders were stratified based on 50% improvement after 4-months (DAPSA50). The BD Rhapsody Whole Transcriptome Approach [1] was applied to prepare cDNA libraries sequenced to a depth of approximately 50.000 reads pr. cells on the Illumina NovaSeq 6000. The Seurat pipeline [2] was implemented for the analysis of gene expression on single cell level. Results A total of 273.515 cells were retrieved after initial quality control. Comparing patient demographics and characteristics at baseline revealed no difference between groups (Table 1). Dimensionality reduction with principal component analysis and additional clustering analysis indicated different phenotypic traits of responders and non-responders to TNFi and IL-17i (Figure 1). The results were limited by the DAPSA50 stratification only requiring 50% improvement at 4-month. Nevertheless, it is believed that scRNAseq can be included to improve PsA patient stratification. Table 1. Patient characteristics All (n=40) TNFi responders (n=12) TNFi non-responders (n=8) IL-17i responders (n=8) IL-17i non-responders (n=12) p-value Sex, female 23 (57.5) 7 (58.3) 4 (50.0) 4 (50.0) 8 (66.7) 0.853 Age 51.9 ±12.1 48.4 ±10.9 54.7 ±11.6 49.6 (17.5) 52.7 ±9.9 0.766 Disease duration 8.1 ±7.4 6.7 ±6.8 10.1 ±10.1 10.4 ±7.9 13.7 ±6.4 0.903 DAPSA 36.5 ±18.5 34.4 ±23.2 34.1 ±13.8 50.5 ±17.3 38.5 ±17.9 0.176 Patient characteristics were presented as number with corresponding percentage or mean with corresponding standard deviations. P-value &lt; 0.05 was considered statically significant. TNFi; Tumour Necrosis Factor alpha inhibitor, IL-17i; Interleukin-17 inhibitor, DAPSA; Disease Activity in Psoriatic Arthritis. Figure 1. Gene expression profiles of DAPSA50 responders and non-responders to IL-17i Heat maps revealing differential gene expression of DAPSA50 responders and non-responders to IL-17i implying the possibility of improved stratification of PsA patients Conclusion High-dimensional data, retrieved from scRNAseq combined with bioinformatical data modelling and clinical knowledge, is important and should possibly be implemented to explore PsA disease heterogeneity and for better stratification of PsA patients prior to initiating available medical therapies. References [1]Shum EY, Walczak EM, Chang C FH. Quantitation of mRNA Transcripts and Proteins Using the BD Rhapsody TM Single-Cell Analysis System. Adv Exp Med Biol 2019;1129:63–79. [2]Satija R, Farrell JA, Gennert D, et al. Spatial reconstruction of single-cell gene expression data. Nat Biotechnol 2015;33:495–502. doi:10.1038/nbt.3192 Acknowledgements We wish to acknowledge all patients participating in this study, our patient research partner Dorte Kongshøj Marcussen for valuable talks during the project and data manager Christian Cato Holm. Additionally, we wish to thank the parties providing funding to complete the study; Eli Lilly, The Danish Rheumatism Association, Elisabeth and Karl Ejnar Nis-Hanssens Mindelegat and Minister Erna Hamiltons Legat for Videnskab og Kunst. Disclosure of Interests Marie Skougaard Speakers bureau: has received speaking fees from Janssen, Grant/research support from: has received research funding from Eli Lilly, Pfizer, The Danish Rheumatism Association and the Danish Psoriasis Association., Clara Drachmann: None declared, Zara Rebecca Stisen: None declared, Sisse B. Ditlev: None declared, Leon Eyrich Jessen: None declared, Lars Erik Kristensen Speakers bureau: from Pfizer, AbbVie, Amgen, UCB, Gilead, Biogen, BMS, MSD, Novartis, Eli Lilly, and Janssen pharmaceuticals, Consultant of: from Pfizer, AbbVie, Amgen, UCB, Gilead, Biogen, BMS, MSD, Novartis, Eli Lilly, and Janssen pharmaceuticals, Grant/research support from: Novo, UCB, Eli Lilly; Novartis and Abbvie